CN1274357A - Antipsychotic substituted piperidine derivatives - Google Patents
Antipsychotic substituted piperidine derivatives Download PDFInfo
- Publication number
- CN1274357A CN1274357A CN98809976A CN98809976A CN1274357A CN 1274357 A CN1274357 A CN 1274357A CN 98809976 A CN98809976 A CN 98809976A CN 98809976 A CN98809976 A CN 98809976A CN 1274357 A CN1274357 A CN 1274357A
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- CN
- China
- Prior art keywords
- compound
- alkyl
- piperidines
- solvate
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 21
- 230000000561 anti-psychotic effect Effects 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 105
- -1 heterocyclic radical Chemical class 0.000 claims description 59
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 45
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 37
- 239000012453 solvate Substances 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 125000001544 thienyl group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- AARAMQPQNNRZQN-UHFFFAOYSA-N Cl.Cl.C=N.C=N.C=N.C=N Chemical compound Cl.Cl.C=N.C=N.C=N.C=N AARAMQPQNNRZQN-UHFFFAOYSA-N 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- HHDQPLCWRRJGDI-SQDRRJMKSA-N C(\C=C/C(=O)O)(=O)O.C=N.C=N.C=N.C=N Chemical compound C(\C=C/C(=O)O)(=O)O.C=N.C=N.C=N.C=N HHDQPLCWRRJGDI-SQDRRJMKSA-N 0.000 claims description 4
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 claims description 3
- JIDACXQPXZWJGW-ODZAUARKSA-N azetidine;(z)-but-2-enedioic acid Chemical compound C1CNC1.OC(=O)\C=C/C(O)=O JIDACXQPXZWJGW-ODZAUARKSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical class OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 claims 1
- 208000028017 Psychotic disease Diseases 0.000 abstract description 2
- 238000013160 medical therapy Methods 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 229960004046 apomorphine Drugs 0.000 description 11
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 230000009194 climbing Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 8
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
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- 239000004480 active ingredient Substances 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000009132 Catalepsy Diseases 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 206010047853 Waxy flexibility Diseases 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940064982 ethylnicotinate Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000015110 jellies Nutrition 0.000 description 4
- 239000008274 jelly Substances 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000002524 organometallic group Chemical group 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- SKYZYDSNJIOXRL-BTQNPOSSSA-N (6ar)-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10,11-diol;hydrochloride Chemical compound Cl.C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 SKYZYDSNJIOXRL-BTQNPOSSSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical group OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 229960003990 apomorphine hydrochloride Drugs 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000002393 azetidinyl group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000000078 claw Anatomy 0.000 description 3
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- 239000003210 dopamine receptor blocking agent Substances 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- 125000005936 piperidyl group Chemical group 0.000 description 3
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- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 2
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- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- AQFATIOBERWBDY-LNQSNDDKSA-N Carboxyatractyloside Chemical compound O1[C@H](CO)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@@H](OC(=O)CC(C)C)[C@@H]1O[C@@H]1CC(C(O)=O)(C(O)=O)[C@H]2CC[C@@]3([C@@H](O)C4=C)C[C@H]4CC[C@H]3[C@]2(C)C1 AQFATIOBERWBDY-LNQSNDDKSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000014094 Dystonic disease Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 101100005318 Mus musculus Ctsr gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- BXLNHFVIUOMFIA-UHFFFAOYSA-N [3-(chloromethyl)phenyl]-piperidin-1-ylmethanone Chemical class ClCC1=CC=CC(C(=O)N2CCCCC2)=C1 BXLNHFVIUOMFIA-UHFFFAOYSA-N 0.000 description 1
- 208000028752 abnormal posture Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000007281 aminoalkylation reaction Methods 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001004 anti-acetylcholinic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 238000006480 benzoylation reaction Methods 0.000 description 1
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical class CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to certain novel substituted piperidine derivatives, to processes for their preparation, to pharmaceutical formulations (I) containing them and to their use in medical therapy, particularly in the treatment of psychotic disorders.
Description
The present invention relates to some new replacements piperidine derivative, its preparation method, contain their pharmaceutical preparation, and they are in medical treatment, the especially application in the treatment mental disorder.
US 2739968 discloses the piperidine derivative of the replacement with antihistamine, spasmolysis, anti-acetylcholine and analgesic activity.US 4666905 and US 4540780 disclose the phenylbenzene methylene derivatives that can be used as antiemetic, antihistaminic agent, lung spasmolytic.
Effectively antipsychotic (spirit suppresses) agent comprises three ring thiodiphenylamine, thioxanthene and hexichol nitrogen and benzamide and butyrophenones.These compounds block d2 dopamine receptors are also blocked the Dopamine HCL conduction.Result as its effect, these compounds can cause the side effect on the characteristic neurological in the male sex, the for example outer side effect of pyramidal tract such as dystonia and dyskinesia (R.J.Baldessarini, 1996, Goodman and Gilman ' s, " pharmacological basis of treatment ", the 9th edition, people such as eds J.G.Hardman).In experimentation on animals, this class side effect self shows as catalepsy.Therefore, it is favourable providing a series of neurolepticss that do not have these weak property side effects.
The invention provides the piperidine derivative of some replacements, it has potent spirit and suppresses active, lives effect but show seldom or do not show any deadlock, therefore can not cause side effect outside the pyramidal tract in therapeutic dose.
Therefore, on the one hand, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof or solvate:
R wherein
1Be benzothienyl, benzofuryl, (wherein said benzothienyl, benzofuryl or naphthyl moiety can be randomly by one or more halogen, C of being selected from for naphthyl
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group replacement of alkenyl), (wherein said thienyl or furyl part are by one or more halogen, C of being selected from for the furyl of thienyl that replaces or replacement
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces); R
2Be that (wherein said phenyl or thienyl part are by one or more C of being selected from for the phenyl of replacement or the thienyl of replacement
1-6The substituting group of alkyl and halogen replaces); R
3Be-(CH
2)
mXCONR
4R
5Or-(CH
2)
mNR
6COR
7, R wherein
4Be hydrogen or C
1-6Alkyl, R
5Be hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
6-12Aryl, C
6-12Aryl C
1-6Alkyl or C
2-9(wherein said alkyl, aryl or heterocyclic radical part can be randomly by one or more halogen, C of being selected from for heterocyclic radical
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces), perhaps R
4And R
5(this heterocyclic radical can be randomly by one or more halogen, C of being selected to form 4-10 unit heterocyclic radical with the nitrogen-atoms that they connected
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces), R
6Be hydrogen or C
1-6Alkyl, R
7Be C
3-6Cycloalkyl, C
3-6Cycloalkyl C
1-6Alkyl, C
6-12Aryl, C
6-12Aryl C
1-6Alkyl or C
2-9(wherein said alkyl, aryl or heterocyclic radical part can be randomly by one or more halogen, C of being selected from for heterocyclic radical
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces), X is key, C
6-12(wherein said aryl or heteroaryl moieties can be randomly by one or more halogen, C of being selected from for aryl or 5 yuan or 6 yuan of heteroaryls
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces); M is an integer 1,2,3 or 4.
The used term alkyl of this specification sheets is meant the straight or branched alkyl.This alkyl comprises methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl and new hexyl.This alkyl is preferably C
1-4Alkyl.The used term cycloalkyl of this specification sheets comprises cyclopropyl and cyclopentyl.
The used term alkenyl of this specification sheets comprises E-type and Z-type alkenyl or their mixture, and when it comprises at least 3 carbon atoms, can be branched alkenyl.This alkenyl is preferably C
1-4Alkenyl.Concrete non-limiting examples of alkenyls comprises vinyl, allyl group, pseudoallyl, butenyl, isobutenyl, pentenyl, isopentene group, hexenyl, dissident's thiazolinyl and neohexene base.
Term halogen comprises chlorine, bromine, fluorine and iodine.
In this manual as the part of group or group and the term aryl of using is meant C
6-12Aryl, and comprise one or two C
6Aromatic ring.The example comprises phenyl, naphthyl and xenyl, especially phenyl.
The used term C of this specification sheets
2-9Heterocyclic radical is meant the C of fragrance, saturated or fractional saturation
2-9Heterocyclic radical.It comprises 1 or 2 C
3-5The ring of fragrant, saturated or fractional saturation, described ring contains one or more (for example 1-3) is selected from the heteroatoms of oxygen, sulphur and nitrogen.Fragrance C
2-9The example of heterocyclic radical comprises thienyl, pyridyl, pyrryl, thiazolyl, furyl, quinolyl and isoquinolyl.Unsaturated C
3-9The example of heterocyclic radical comprises piperidyl, pyrrolidyl and azetidinyl.
5 yuan or 6 yuan heteroaryls of term are meant and contain heteroatomic 5 yuan or 6 yuan of aromatic nucleus that one or more (for example 1-3, preferred 1) are selected from oxygen, sulphur and nitrogen.For example thienyl, pyridyl, pyrryl, thiazolyl and furyl.
4 yuan of-10 yuan of heterocycles of term are meant 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan of rings of the heteroatomic fragrance that contains one or more (for example 1-3, preferred 1) and be selected from oxygen, sulphur and nitrogen, saturated or fractional saturation.The example of this fragrant heterocyclic radical comprises thienyl, pyridyl, pyrryl, thiazolyl, furyl, quinolyl and isoquinolyl.The example of this unsaturated heterocycle base comprises piperidyl, pyrrolidyl and azetidinyl.
The thienyl of benzothienyl, benzofuryl, naphthyl, replacement and the furyl of replacement comprise 2-benzothienyl and 3-benzothienyl, 2-benzofuryl and 3-benzofuryl, 2-naphthyl and 3-naphthyl, the 2-thienyl of replacement, the 3-thienyl of replacement, the 2-furyl of replacement and the 3-furyl of replacement.Substituting group on benzothienyl, benzofuryl, naphthyl, thienyl and the furans basic ring can be positioned on any available position of this ring.The specific examples of ring substituents comprises fluorine, chlorine and methoxyl group.
The present invention also comprises formula (I) compound or pharmaceutically acceptable salt thereof or solvate, wherein: (i) R
1Be that (substituting group on the wherein said thienyl part is C for the thienyl of benzothienyl or replacement
1-6Alkyl, for example methyl and ethyl); (ii) R
2It is the phenyl (substituting group on the wherein said phenyl moiety is a halogen, for example fluorine) that replaces; (iii) R
3Be-(CH
2)
mXCONR
4R
5, R wherein
4And R
5Form 4 yuan, 5 yuan or 6 yuan of heterocyclic radicals with the nitrogen-atoms that they connected, for example piperidyl, pyrrolidyl and azetidinyl, X is key or C
6Aryl such as phenyl, and m is integer 1,2,3 or 4, especially 1 or 4; (iv) R
3Be-(CH
2)
mNR
6COR
7, R wherein
6Be hydrogen, R
7Be C
3-6Cycloalkyl such as cyclopropyl, C
3-6Cycloalkyl C
1-6Alkyl such as cyclopentyl-methyl, C
6Aryl can be randomly by one or more C
1-6Alkyl replaces, for example can be randomly by methyl substituted phenyl, and m is an integer 1,2,3 or 4, especially 2,3 or 4; (v) R
1, R
2And R
3Definition with (i)-(iv) described.
Other example of top formula (I) compound is included in the compound of describing in embodiment 2 and 3.
Preferred The compounds of this invention comprises following formula (I) compound or pharmaceutically acceptable salt thereof or solvate, and wherein X is C
6-12(wherein said aryl or heteroaryl moieties can be randomly by one or more halogen, C of being selected from for aryl or 5 yuan or 6 yuan of heteroaryls
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces).
Particularly preferred The compounds of this invention is: (4-thiotolene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] piperidines (1: 1) ethane dicarboxylic acid salt; The 1-[4-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] the tetramethyleneimine dihydrochloride; The 1-[4-[4-[(3-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] piperidine hydrochlorate; The 1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] piperidines; The 1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] pyrrolidine hydrochloride; The 1-[3-[4-[(4-fluorophenyl) (thionaphthene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the piperidines maleate; The 1-[3-[4-[(4-fluorophenyl) (thionaphthene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the tetramethyleneimine maleate; The 1-[3-[4-[(4-fluorophenyl) (4-ethylthiophene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the piperidines fumarate; The 1-[3-[4-[(4-fluorophenyl) (4-ethylthiophene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the tetramethyleneimine dihydrochloride; 4,4-dimethyl-1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the azetidine maleate; With their pharmacologically acceptable salt and solvate.
For treatment was used, the salt of formula (I) compound was that wherein counter ion are the acceptable salt of medicine.Yet pharmaceutically unacceptable acid salt also may have practical value, for example can use in the process of preparation or the pharmaceutically acceptable compound of purifying.No matter whether all salt of The compounds of this invention be pharmaceutically useful, all is included in the scope of the present invention.
The example of pharmaceutically acceptable acid additive salt comprises by following acid derives and next salt: mineral acid, for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acid, for example tartrate, acetate, trifluoroacetic acid, citric acid, oxysuccinic acid, lactic acid, toxilic acid, propanedioic acid, fumaric acid, phenylformic acid, xitix, propionic acid, oxyacetic acid, glyconic acid, succsinic acid, methylsulfonic acid and aryl sulfonic acid such as Phenylsulfonic acid or tosic acid.
Preferred salt of the present invention comprises hydrochloride, maleate, succinate and fumarate.
Solvate of the present invention comprises hydrate.
On the other hand, the invention provides be used for the treatment of, especially for formula (I) compound and the pharmacologically acceptable salt and the solvate of treatment or prevention of psychotic disorders such as schizophrenia, manic, hyperaction, substance abuse, vomiting and schizophrenia type obstacle.
The present invention also comprises treating to suffer from or easily suffer from the animal of the mental disorder that comprises arbitrary above-mentioned disease, as comprises people's mammiferous method, comprises formula (I) compound or pharmaceutically acceptable salt thereof or solvate administration with significant quantity.
On the other hand, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof or solvate is used for the treatment of or prevents application in the medicine of arbitrary above-mentioned disease in preparation.
Certainly, also being called as formula (I) compound or pharmaceutically acceptable salt thereof of active ingredient or solvate in this manual is to reach the required amount of result of treatment will change with age of particular compound, route of administration, receptor and physical appearance and the concrete obstacle or the disease of being treated.
For arbitrary above-mentioned disease, suitable per daily dose is 0.001-25mg/kg receptor (for example people) body weight/day, is preferably the 0.1-10mg/kg body weight/day, most preferably is the 0.25-5mg/kg body weight/day.Required dosage can be divided into 1,2,3,4,5 or 5 with the administration in one day appropriate intervals of dosage last time.
Though active ingredient can be individually dosed, preferably its form with pharmaceutical preparation is used.Therefore, the present invention also provides pharmaceutical preparation, wherein contains formula (I) compound or pharmaceutically acceptable salt thereof or solvate and pharmaceutically acceptable carrier, and can randomly contain other therapeutical agent.Carrier is with other component compatibility of preparation with must be " acceptable " aspect the curee not being damaged.
Preparation comprises the preparation that is suitable for oral administration, rectal administration, nose administration, topical (comprising transdermal administration, cheek administration (buccal) and sublingual administration), vagina administration or parenteral administration (comprising subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration and glass vivo medicine-feeding).Preparation can make by the well-known method of pharmacy field, for example use " Remington pharmacology " people such as Gennaro (Remington ' s PharmaceuticalSciences) (the 18th edition, Mack publishing company, 1990, especially referring to the 8th part: pharmaceutical preparation and production thereof) the middle method of describing.These methods comprise active ingredient and the carrier that is made of one or more auxiliary components blended step mutually.Described auxiliary component comprises that this area uses auxiliary material always, for example weighting agent, tackiness agent, thinner, disintegrating agent, lubricant, tinting material, seasonings and wetting agent.
The preparation that is suitable for oral administration can be made the discrete unit that contains the predetermined amount active ingredient respectively, for example pill, tablet or capsule; Pulvis or granula; Solution or suspension agent.Active ingredient can also be prepared the form of patent medicine group or paste, perhaps active ingredient is included in the liposome.
The rectal administration preparation can be made suppository or enema.
For the parenteral administration preparation, appropriate formulation comprises water or non-water aseptic injection.This class preparation can be contained in single dose or multi-dose container such as sealed vial and the ampoule, and can preserve under the condition of lyophilize (lyophilize), only need add before use sterile liquid carrier for example water get final product.
Be suitable for comprising dust agent or sprays by the preparation of inhalation in the nose, it can seal aerosol, atomizer or insufflator by supercharging and produce with doses.
The present invention also comprises the following method of preparation formula (I) compound.
Formula (I) compound can make according to the various ordinary methods of organic chemistry filed.Raw materials usedly be known and can obtain easily that perhaps himself can make by routine techniques from chemical company.For example, can be used in " chemistry of heterocyclic compound " (The Chemistry ofHeterocyclic Compounds), the 44th volume, " thiophene and derivative thereof ", 1-5 part, Ed S.Gronowitz J.Wiley and Sons, with A.R.Katritsky and C.W.Rees, " comprehensive heterocyclic chemistry " (Comprehensive Heterocyclic Chemistry), the 4th part, Ed C.W.Bird and G.H.Cheesman, the method for describing in the Pergamon press is synthesized described compound.
For example, formula (I) compound can by with US 4540780 in the similar method of disclosed method make.
In following description, except as otherwise noted, else symbol R
1, R
2, R
3, R
4, R
5, R
6, R
7, X and m definition with in formula (I), describe identical.
Formula (I) compound can be by making formula (II) compound
With formula R
3The reaction of-L compound makes, and wherein L is suitable leavings group, for example halogen such as chlorine, bromine or iodine, or methylsulfonyl or tosyl group.This reaction generally at solvent for example in the presence of toluene or the ethanol, carry out under 60-110 ℃ of temperature.
Generally be in room temperature or be at most under the comparatively high temps of reflux temperature, acid scavenger for example in the presence of triethylamine or the salt of wormwood, in toluene or ethanol, formula (II) compound and reagent such as 1-(3-monochloromethyl benzoyl) piperidines, 1-(3-monochloromethyl benzoyl) tetramethyleneimine, (4-halogen-1-oxo butyl) piperidines (wherein halogen comprises chlorine, bromine or iodine) or corresponding methylsulfonyl or tolylsulfonyl radical derivative are reacted as (4-mesyloxy-1-oxo butyl) piperidines.
Perhaps, by formula (III) amine acidylate can be made formula (I) compound.
For example, with formula (III) compound and suitable formula R
7The COCl acyl chloride reaction can make formula (I) compound.
By with the currently known methods in the chemical literature, for example methylate by the formic acid pyrolysis or use the reductive alkylation method with iodoethane or before acidylate, the general is R wherein accordingly
6Formula (III) the compound amino-alkylation that is hydrogen can make wherein R
6Be formula (III) the compound amine of alkyl.
After aforesaid method, when must or need, can carry out one or more following further steps with random order therein: (i) pharmacologically acceptable salt or the solvate with formula (I) compound transforms an accepted way of doing sth (I) compound.(ii) with the pharmacologically acceptable salt of formula (I) compound or the another kind of pharmacologically acceptable salt or the solvate of a solvate conversion accepted way of doing sth (I) compound.(iii) formula (I) compound is transformed the pharmacologically acceptable salt or the solvate of an accepted way of doing sth (I) compound.
The dehydration of through type (IV) compound can make formula (II) compound easily,
R wherein
8It is for example trityl of hydrogen or nitrogen-protecting group.Generally be with mineral acid hydrochloric acid or dewater for example with phosphorus oxychloride.Can carry out this reaction easily with the dehydration of alcohols standard conditions.For example, can under the 80-120 ℃ of temperature, at appropriate solvent for example in the presence of the pyridine, carry out this reaction with phosphorus oxychloride.
Other method that can use those skilled in the art maybe can find easily from chemical literature is as everyone knows carried out this dehydration reaction, comprises using sulfuric acid, 4-toluene sulfonic acide, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, thionyl chloride is dewatered or using Martin sulfane (sulphurane) dewatering agent dewater (adopting appropriate solvent in case of necessity).
The method of using those skilled in the art maybe can find easily from chemical literature as everyone knows can be with R wherein
8Be nitrogen-protecting group such as trityl above-mentioned formula (IV) compound simultaneously or successively dehydration and deprotection to form formula (II) compound.
Handle the formula V compound with suitable organometallic reagent and can make formula (IV) compound,
R wherein
8Be hydrogen or nitrogen-protecting group, described organometallic reagent for example is a Grignard reagent, or derived from R
2The lithium reagent of-L, wherein L is suitable halogen such as bromine or chlorine, or derived from the lithium reagent of activatory aryl hydrogen atom.For example, under the standard reaction condition, handle the formula V compound, can make wherein R easily with the phenyl magnesium halide that suitable halogen replaces
2Formula (IV) compound of the phenyl that is replaced by halogen atom.
Formula (IV) compound also can make by handling formula (VI) compound with suitable organometallic reagent,
R wherein
8Be hydrogen or nitrogen-protecting group, described organometallic reagent for example is a Grignard reagent, or derived from R
1The lithium reagent of-L, wherein L is suitable halogen such as bromine or chlorine, or derived from the lithium reagent of activatory aryl hydrogen atom.This reaction generally under-60～67 ℃ of temperature, transmit solvent in nonpolar aprotic and for example carry out in the presence of ether or the tetrahydrofuran (THF).
The formula V compound can make by the currently known methods in the chemical literature.For example, as described in embodiment 1, the chlorination of the halogeno-benzene formyl radical thiophene by suitable replacement can make wherein R
1Be 4-chloro-thienyl or 2, the formula V compound of 3-dichloro-thiophene base.The commercially available acquisition of these compounds, perhaps available means known in the art make, and for example can pass through thiophene or R
1Other group of representative carries out the friedel-crafts benzoylation and makes.
Formula V and (VI) compound can make by for example suitable Grignard reagent being added in N-methyl iso ethyl nicotinate or the N-trityl iso ethyl nicotinate.N-methyl iso ethyl nicotinate or the commercially available acquisition of N-trityl iso ethyl nicotinate, perhaps available means known in the art are made by the compound of commercially available acquisition.
Perhaps, R wherein
8Be acyl group or hydrogen and R
2Formula (VI) compound that is the 4-fluorophenyl can be according at " pharmaceutical chemistry magazine " (J.Med.Chem.), and 1970,
13, the method for describing in 1 makes.R wherein
8The formula V compound that is trityl can be by R wherein
8The formula V compound that is hydrogen makes, and for example uses the method for describing among the embodiment 4 hereinafter, by R wherein
8The formula V compound and the trityl bromine reaction that are hydrogen can make wherein R
8It is the formula V compound of trityl.Above-mentioned formula R
3-L compound can for example be used those skilled in the art's currently known methods, makes by making suitable carbonyl chloride and suitable amine reaction.
Above-mentioned formula (III) compound can make like this: adopt means known in the art, with formula (II) compound and suitable haloalkyl phthalic imidine reaction, handle gained N-alkyl phthalic imide intermediate with hydrazine then.
Perhaps, wherein m is 2 and R
6Formula (III) compound that is hydrogen can make like this: for example in the presence of salt of wormwood and acetonitrile or DMF, handle formula (II) compound with bromoacetonitrile, subsequently with being suitable for that nitrile is reduced into the reagent of amine with this intermediate reduction.Appropriate reductant comprises for example lithium aluminum hydride of hydride.
By using suitable alkali, for example alkali metal hydroxide, alkaline earth metal hydroxides or ammonium hydroxide, perhaps suitably organic acid or mineral acid for example hydrochloric acid, fumaric acid or toxilic acid are handled formula (I) compound and can be made salt of the present invention.
The present invention also comprises all new intermediates, especially formula (II) compound of describing in this manual.
Following embodiment illustrates for example, and never is to limit the scope of the invention by any way.Embodiment 1
The 4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidine hydrochlorate
Under-25 ℃, nitrogen atmosphere, in methylene dichloride (690ml) solution with 4-(the 1-ethanoyl piperidyl) carbonyl chloride (50g) that successively methylene dichloride (300ml) solution of aluminum chloride (71g) powder and 2-bromo-3 methyl thiophene (50g) was added to continuous stirring in 17 minutes.After 30 minutes, in reaction, drip water (240ml), simultaneously temperature of reaction is risen to approximately+20 ℃.Behind the restir 30 minutes, inorganic components is removed by filtering with the dicalite pad.Separate each layer, organic layer is washed with water 2 times, dry (Na
2SO
4), reduction vaporization afterwards.(73g) carries out chromatogram purification with crude product, obtained 2-(5-bromo-4-thiotolene base)-4-(1-ethanoyl piperidines) ketone (62.2g); Fusing point 105-108.5 ℃ (decomposition temperature).
Under 60 ℃ and nitrogen atmosphere, zinc powder (22g), sodium iodide (11g), triphenylphosphine (16.5g) and nickel chloride hexahydrate (2.56g) suspension in the methyl alcohol (340ml) (making in 2 hours by methyl alcohol is seethed with excitement under nitrogen gas stream) of deoxidation was stirred 15 minutes.The solution of top gained bromo compound (62.2g) in the methyl alcohol (150ml) of deoxidation is added in this mixture, with reaction mixture boiling reflux 22 hours under nitrogen atmosphere.To react cooling, inorganic components be removed by filtering with the dicalite pad.With the filtrate evaporation, resistates is dissolved in methylene dichloride.Use successively rare mineral acid, water with this solution washing to neutral, dry (Na
2SO
4), and reduction vaporization is to doing.Crude product (61.3g) by purified by flash chromatography, with methylene dichloride/ether recrystallization, has been obtained 2-(4-thiotolene base)-4-(1-ethanoyl piperidines) ketone (41.2g) in two batches; Fusing point 120-125 ℃.The solution of this ketone (41.2g) in 5N hydrochloric acid (140ml) was refluxed 16 hours, and reduction vaporization is used toluene and remainder water azeotropic then.Resistates is developed with ether, obtained crude product (38.8g), by filtering its separation.With the mixture recrystallization of methyl alcohol and ether, obtained 2-(4-thiotolene base)-4-piperidines ketone hydrochloride (29.5g) in two batches; Fusing point 217.5-218.5 ℃ (more than 200 ℃ time crystal formation change).
With the alkalization of the aqueous solution of top gained hydrochloride (28g), and under 0 ℃ and nitrogen atmosphere, the solution of product (24.1g) in methylene dichloride (240ml) and triethylamine (48ml) that will alkalize stirs.With trityl chloride (33.7g) so that temperature of reaction maintains 0 ± 2 ℃ speed adds in batches.After 30 minutes, water (240ml) dilutes this mixture carefully, and is extracted in the methylene dichloride.With the extraction liquid washing, dry (Na
2SO
4), and reduction vaporization is with heptane part instead of methylene chloride and make its crystallization.Crystal is filtered, and the mixture washing with 4: 1 heptane and methylene dichloride has obtained 2-(4-thiotolene base)-4-(1-trityl piperidines) ketone (46.9g); Fusing point 219-221 ℃ (decomposition).
Under agitation, monobromethane (1.5ml) is added in the suspension of magnesium chips (6.4g) in containing the anhydrous diethyl ether of iodine crystal (100ml).The temperature maintenance of this thermopositive reaction at 32-36 ℃, is added anhydrous diethyl ether (170ml) solution of 4-bromofluoro benzene (29ml) simultaneously carefully.The gained mixture was leniently refluxed 30 minutes, be cooled to 0 ℃ then.Be added in this mixture with 15 minutes anhydrous diethyl ether (280ml) drips of solution top gained ketone (23.5g), simultaneously with temperature maintenance at 0-5 ℃.With about 30 minutes temperature of reaction is risen to room temperature then, use the ethyl acetate extraction product.Extraction liquid is washed with water dry (Na
2SO
4), and reduction vaporization, obtained jelly (32.4g), this jelly is dissolved in the mixture of acetate (261ml) and water (130ml), this solution was refluxed 18 hours.Add entry (130ml), reaction is cooled to below 5 ℃.Filtering solid matter (triphenylcarbinol) is with filtrate evaporated under reduced pressure extremely very small volume., with the alkalization of gained resistates product is extracted in the ethyl acetate with strong aqua.Extraction liquid is washed dry (Na with sodium chloride aqueous solution
2SO
4), and reduction vaporization has obtained gummy residue (15.0g) to doing.The methanol solution of hydrogenchloride is added in the diethyl ether solution of this resistates, makes its crystallization, obtained
The 4-[(4-fluorophenyl) (4-thiotolene-2- Base) methylene radical] piperidine hydrochlorate(9.0g); Fusing point 191-206 ℃ (decomposition).
Embodiment 2The 1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] piperidines (
2a)
3-chloromethyl benzoic acid chlorides (1.45ml) is added in triethylamine (2ml) solution of piperidines (1ml), this mixture was stirred 45 minutes under 5 ℃, nitrogen atmosphere.Add entry, use the dichloromethane extraction product, and extraction liquid is washed with water,, obtained 1-(3-chloromethylbenzene formyl radical) piperidines (2.32g), be oily matter with dried over sodium sulfate and evaporation.
With this benzoyl piperidines (2.3g), embodiment 1 gained 4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines (3g) and triethylamine (3ml) solution in toluene refluxed 5 hours.With the mixture cooling, add entry, separate each layer, isolate toluene layer, use the salt water washing, with dried over sodium sulfate and evaporation.(5.6g) is dissolved in methylene dichloride with gained oily matter, carries out chromatogram purification with silicon-dioxide.With the methylene dichloride/ammonium hydroxide that contains incremental change methyl alcohol (1%) wash-out,, obtained the evaporation of gained elutriated fraction
Title compound(4.36g).Handle the diethyl ether solution of this compound with the diethyl ether solution of hydrogenchloride.To precipitate and collect and drying, obtain its hydrochloride (3.6g), fusing point 118-142 ℃.
Made following compound in a similar manner with suitable haloalkyl acyl chlorides:
2b: (4-thiotolene-2-yl) methylene radical 1-[3-[4-[(4-fluorophenyl)] piperidines-1-ylmethyl] benzoyl] pyrrolidine hydrochloride, fusing point 118-127 ℃
2c: (4-ethylthiophene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] the piperidines dihydrochloride, m/e 454
2d: (4-ethylthiophene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] the tetramethyleneimine dihydrochloride, 167.4 ℃ of fusing points
2e: (thionaphthene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] the piperidines dihydrochloride, fusing point 117-121 ℃
2f: (thionaphthene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] the tetramethyleneimine maleate, m/e 462
2g: (thionaphthene-2-yl) methylene radical 1-[3-[4-[(4-fluorophenyl)] piperidines-1-ylmethyl] benzoyl] the piperidines maleate, fusing point 179-183 ℃
2h: (thionaphthene-2-yl) methylene radical 1-[3-[4-[(4-fluorophenyl)] piperidines-1-ylmethyl] benzoyl] the tetramethyleneimine maleate, fusing point 157-163 ℃
2i: (4-ethylthiophene-2-yl) methylene radical 1-[3-[4-[(4-fluorophenyl)] piperidines-1-ylmethyl] benzoyl] the piperidines fumarate, 173.4 ℃ of fusing points
2j: (4-ethylthiophene-2-yl) methylene radical 1-[3-[4-[(4-fluorophenyl)] piperidines-1-ylmethyl] benzoyl] the tetramethyleneimine dihydrochloride, 167.4 ℃ of fusing points
2k: 4,4-dimethyl-1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the azetidine maleate, 173.7 ℃ of fusing points
2l: (4-thiotolene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] piperidines (1: 1) ethane dicarboxylic acid salt, fusing point 172-174 ℃
2m: (4-thiotolene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] the tetramethyleneimine dihydrochloride, fusing point 144-146 ℃
2n: (4-thiotolene-2-yl) methylene radical 1-[4-[4-[(3-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] piperidine hydrochlorate, fusing point 148-154 ℃
Embodiment 3 Preparation N-[4-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-base fourth Base] the benzamide oxalate(
3a)
With the 4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines (2g), 4-brombutyl phthalic imidine (1.76g) and the solution of triethylamine (2ml) in toluene (20ml) refluxed 4 hours.With this solution cooling, dilute with water is isolated toluene layer, and evaporation has obtained phthalic imidine (3g), is dark oily matter, and it is with oxalate form purifying.
Solution in ethanol (20ml) refluxed 2 hours with aforementioned phthalic imidine (1.88g) and hydrazine hydrate (0.37ml).Reduction vaporization is removed ethanol, adds entry and yellow soda ash.Use the dichloromethane extraction product, extraction liquid is washed with water, dry and evaporation has obtained 1-(the amino butyl of 4-)-4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines (1.16g), be oily matter.
Benzoyl chloride is added in the solution of aforementioned amine in the methylene dichloride that contains triethylamine (1ml), with this solution stirring at room 2 hours.Add entry and methylene dichloride in this solution, separate each layer, dry and evaporation has obtained dark jelly (1.56g) with dichloromethane layer.This jelly is carried out chromatogram purification with silicon-dioxide, use the methylene dichloride wash-out that contains incremental change methyl alcohol, and purified product is changed into oxalate, with this oxalate crystallization, obtained title compound with methanol, fusing point 95-98 ℃.
Made following compound in a similar manner:
3b: (4-thiotolene-2-yl) methylene radical N-[3-[4-[(4-fluorophenyl)] piperidines-1-yl] propyl group] benzamide hydrochloride salt, fusing point 95-97 ℃
3c: (4-thiotolene-2-yl) methylene radical 4-methyl-N-[2-[4-[(4-fluorophenyl)] piperidines-1-yl] ethyl] the benzamide oxalate, fusing point 189-191 ℃
3d: (4-thiotolene-2-yl) methylene radical 4-methyl-N-[2-[4-[(4-fluorophenyl)] piperidines-1-yl] ethyl]-N-methyl-benzamide, fusing point 114-116 ℃
3e: (4-thiotolene-2-yl) methylene radical N-[2-[4-[(4-fluorophenyl)] piperidines-1-yl] ethyl] the cyclopropyl carboxamide oxalate, fusing point 98-101 ℃
3f: (4-thiotolene-2-yl) methylene radical N-[2-[4-[(4-fluorophenyl)] piperidines-1-yl] ethyl] cyclopentyl methane amide oxalate, fusing point 145-148 ℃
Embodiment 4
The apomorphine that in mouse, the carries out test of climbing
Dopamine-receptor antagonist in rodent, suppress by dopamine agonist for example the ability of the behavior effect that causes of apomorphine be that these medicines of prediction good standard that spirit suppresses to render a service in the mankind is (referring to Bowman and M.J.Rand, " pharmacology textbook " (Textbook ofPharmacology), the 2nd edition, 1980,15,6).Relevant especially in this respect test is, measures dopamine antagonist and suppress the test (ACT) of climbing of apomorphine by the ability of subcutaneous or the behavior of climbing that the oral administration apomorphine causes in mouse.In this test, the activity of measuring behind system or the oral administration has been widely used as that spirit suppresses active, promptly the active Prediction Parameters of anti-schizophrenia is (referring to, people such as J.T.Strupczewski for example, " pharmaceutical chemistry magazine " (J.Med.Chem.), 1995,38,1119).Mouse with the apomorphine hydrochloride administration trends towards taking vertical position to stand or climb along the wall of silk screen cylindrical drum.This behavior of climbing is considered to because due to the stimulation Dopamine Receptors of apomorphine mediation.A lot of this behaviors of climbing of drug influence, but dopamine-receptor antagonist suppresses the behavior of climbing with the dosage that does not influence locomotor activity and/or sports coordination usually in mouse.The test compounds of regulating this behavior of climbing may have spirit and suppress active.
In mouse with various treatment random assignments.Each test is made of 1+n treatment group: the 1st, and the control group of forming by 12 subcutaneous mouse of accepting apomorphine and carrier, or subcutaneously accept the control group that apomorphine and the oral mouse of accepting carrier are formed by 12; The compound group that n (normally 4) is made up of 12 subcutaneous mouse of accepting apomorphine and test compounds, or subcutaneously accept the compound group that apomorphine and the oral mouse of accepting test compounds are formed by 12.
Test divides 3 to take turns and carry out, and whenever takes turns 20 mouse.With mouse mark and weighing, test compounds or carrier subcutaneous administration and mouse is placed size is the Macrolon cage of 17 * 11 * 13cm, each cage is put 5 mouse, perhaps test compounds or carrier oral administration and mouse is placed size is the Macrolon cage of 29 * 11 * 13cm, each cage is put 5 mouse.After 30 minutes, with dosage the mouse administration to carrier or test compounds subcutaneous administration handle of apomorphine hydrochloride with 0.75mg/kg, perhaps with dosage the mouse administration to carrier or test compounds oral administration handle of apomorphine hydrochloride with 0.75mg/kg, and mouse is placed on alone in the silk screen cylindrical drum (diameter is 12cm, high 14cm).
After handling 10 minutes with apomorphine, observe the behavior of climbing of each mouse, and keep the score according to following grading system: 4 claws are taken off at wall last 1 minute 3 or 4 claws at base plate last 0 minute 1 or 2 claws and were taken off in wall last 2 minute
After 20 minutes, observe the behavior of climbing and marking with the apomorphine processing once more.For each treatment group, determine the average mark of every mouse.The score of control group should be at least 1.0, otherwise just gives up this test.To represent the net result of each group with respect to the per-cent of control group.
The test-results of test compounds is (test compounds subcutaneous administration) as shown in Table I.Table I
Compound ACT (ED 50 ) mg/kg (subcutaneous administration)Compound
210.3 compound
2m0.14 compound
2n0.34
2l=1-[4-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] piperidines (1: 1) ethane dicarboxylic acid salt
2m=1-[4-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] the tetramethyleneimine dihydrochloride
2n=1-[4-[4-[(3-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] piperidine hydrochlorate
Embodiment 5
Rat catalepsy shape
Use male Wistar rat (100-125g, Olac UK) to carry out deadlock and live test.(people such as Broekkamp, Naunyn-Schmiedeberg ' s Arch.Pharmacol. as mentioned above
338, 191,1988) and estimate the catalepsy shape.In brief, in 6 different viewing tests, test rat, wherein rat is placed with abnormal posture, just divided in one minute keeping this to force 10 seconds meter of posture.The posture of forcing has: vertically be close on the grid; Upright and fore paw is supported on the high upholder; Make the back leg elongation; The back of the body is placed down; In mouth, place spatula; With in the silk screen cylindrical drum, rotate.
Can reach best result 6 minutes in theory.With drug administration 60 minutes and 120 minutes postevaluation catalepsy shapes.By two-way variance analysis (2 way ANOVAR) with carry out NewmanKools post hoc check (Newman Kools post hoc test) afterwards and come evaluating data, and calculate ED
50Value (Table II).Table II
Compound CATR (ED 50 ) mg/kgCompound
2m＞7mg/kg compound
2n＞17mg/kg
Claims (10)
1. formula (I) compound or pharmaceutically acceptable salt thereof or solvate:
R wherein
1Be benzothienyl, benzofuryl, (wherein said benzothienyl, benzofuryl or naphthyl moiety can be randomly by one or more halogen, C of being selected from for naphthyl
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group replacement of alkenyl), (wherein said thienyl or furyl part are by one or more halogen, C of being selected from for the furyl of thienyl that replaces or replacement
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces); R
2Be that (wherein said phenyl or thienyl part are by one or more C of being selected from for the phenyl of replacement or the thienyl of replacement
1-6The substituting group of alkyl and halogen replaces); R
3Be-(CH
2)
mXCONR
4R
5Or-(CH
2)
mNR
6COR
7, R wherein
4Be hydrogen or C
1-6Alkyl, R
5Be hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
6-12Aryl, C
6-12Aryl C
1-6Alkyl or C
2-9(wherein said alkyl, aryl or heterocyclic radical part can be randomly by one or more halogen, C of being selected from for heterocyclic radical
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces), perhaps R
4And R
5Form 4-10 unit heterocyclic radical with the nitrogen-atoms that they connected, and this heterocyclic radical can be randomly by one or more halogen, C of being selected from
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces, R
6Be hydrogen or C
1-6Alkyl, R
7Be C
3-6Cycloalkyl, C
3-6Cycloalkyl C
1-6Alkyl, C
6-12Aryl, C
6-12Aryl C
1-6Alkyl or C
2-9(wherein said alkyl, aryl or heterocyclic radical part can be randomly by one or more halogen, C of being selected from for heterocyclic radical
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The group of alkenyl replaces), X is key, C
6-12(wherein said aryl or heteroaryl moieties can be randomly by one or more halogen, C of being selected from for aryl or 5 yuan or 6 yuan of heteroaryls
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces); M is an integer 1,2,3 or 4.
2. the compound or pharmaceutically acceptable salt thereof of claim 1 or solvate, wherein R
1Be that (substituting group on the wherein said thienyl part is C for the thienyl of benzothienyl or replacement
1-6Alkyl).
3. the compound or pharmaceutically acceptable salt thereof of claim 1 or solvate, wherein R
2It is the phenyl (substituting group on the wherein said phenyl moiety is a halogen) that replaces.
4. the compound or pharmaceutically acceptable salt thereof of claim 1 or solvate, wherein R
3Be-(CH
2)
mXCONR
4R
5, R wherein
4And R
5Form 4 yuan, 5 yuan or 6 yuan of heterocyclic radicals with the nitrogen-atoms that they connected, X is key or C
6Aryl, and m is an integer 1,2,3 or 4; Perhaps R
3Be-(CH
2)
mNR
6COR
7, R wherein
6Be hydrogen, R
7Be can be randomly by one or more C
1-6The C that alkyl replaces
3-6Cycloalkyl, C
3-6Cycloalkyl C
1-6Alkyl, C
6Aryl, m are integers 1,2,3 or 4.
5. the compound or pharmaceutically acceptable salt thereof of claim 1 or solvate, wherein R
1Be that (substituting group on the wherein said thienyl part is C for the thienyl of benzothienyl or replacement
1-6Alkyl); R
2It is the phenyl (substituting group on the wherein said phenyl moiety is a halogen) that replaces; R
3Be-(CH
2)
mXCONR
4R
5, R wherein
4And R
5Form 4 yuan, 5 yuan or 6 yuan of heterocyclic radicals with the nitrogen-atoms that they connected, X is key or C
6Aryl, and m is integer 1,2,3 or 4, perhaps R
3Be-(CH
2)
mNR
6COR
7, R wherein
6Be hydrogen, R
7Be can be randomly by one or more C
1-6The C that alkyl replaces
3-6Cycloalkyl, C
3-6Cycloalkyl C
1-6Alkyl, C
6Aryl, m are integers 1,2,3 or 4.
6. the compound or pharmaceutically acceptable salt thereof of claim 1 or solvate, wherein X is C
6-12(wherein said aryl or heteroaryl moieties can be randomly by one or more halogen, C of being selected from for aryl or 5 yuan or 6 yuan of heteroaryls
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group and C
1-6The substituting group of alkenyl replaces).
7. according to each compound or pharmaceutically acceptable salt thereof or solvate of claim 1-5, wherein said compound or pharmaceutically acceptable salt thereof or solvate are selected from: (4-thiotolene-2-yl) methylene radical 1-[4-[4-[(4-fluorophenyl)] piperidines-1-yl]-1-oxo butyl] piperidines (1: 1) ethane dicarboxylic acid salt; The 1-[4-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] the tetramethyleneimine dihydrochloride; The 1-[4-[4-[(3-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-yl]-1-oxo butyl] piperidine hydrochlorate; The 1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] piperidines; The 1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] pyrrolidine hydrochloride; The 1-[3-[4-[(4-fluorophenyl) (thionaphthene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the piperidines maleate; The 1-[3-[4-[(4-fluorophenyl) (thionaphthene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the tetramethyleneimine maleate; The 1-[3-[4-[(4-fluorophenyl) (4-ethylthiophene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the piperidines fumarate; The 1-[3-[4-[(4-fluorophenyl) (4-ethylthiophene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the tetramethyleneimine dihydrochloride; 4,4-dimethyl-1-[3-[4-[(4-fluorophenyl) (4-thiotolene-2-yl) methylene radical] piperidines-1-ylmethyl] benzoyl] the azetidine maleate; With their pharmacologically acceptable salt and solvate.
8. be used for the treatment of as claim 1-5 each described formula (I) compound or pharmaceutically acceptable salt thereof or solvate.
9. pharmaceutical preparation wherein contains each described formula (I) compound or pharmaceutically acceptable salt thereof or solvate just like claim 1-7, and pharmaceutically acceptable carrier.
10. preparation is as the method for each described formula (I) compound of claim 1-7, and this method comprises: (A) make formula (II) compound
With formula R
3The reaction of-L compound, wherein R
1And R
2Definition such as claim 1 described in, L is suitable leavings group, (B) makes formula (III) amine and suitable acylation reaction,
R wherein
1, R
2, and R
6Definition such as claim 1 described in, afterwards or simultaneously, can randomly carry out one or more following conversions: (i) pharmacologically acceptable salt or the solvate with formula (I) compound transforms an accepted way of doing sth (I) compound; (ii) with the pharmacologically acceptable salt of formula (I) compound or another pharmacologically acceptable salt or the solvate of a solvate conversion accepted way of doing sth (I) compound; (iii) formula (I) compound is transformed the pharmacologically acceptable salt or the solvate of an accepted way of doing sth (I) compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97203107 | 1997-10-07 | ||
| EP97203107.4 | 1997-10-07 |
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| Publication Number | Publication Date |
|---|---|
| CN1274357A true CN1274357A (en) | 2000-11-22 |
Family
ID=8228799
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98809976A Pending CN1274357A (en) | 1997-10-07 | 1998-10-07 | Antipsychotic substituted piperidine derivatives |
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|---|---|
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| EP (1) | EP1021440A2 (en) |
| JP (1) | JP2001519430A (en) |
| KR (1) | KR20010024441A (en) |
| CN (1) | CN1274357A (en) |
| AU (1) | AU747393B2 (en) |
| BR (1) | BR9812862A (en) |
| CA (1) | CA2305277A1 (en) |
| HU (1) | HUP0004796A3 (en) |
| IL (1) | IL135195A0 (en) |
| NO (1) | NO20001778L (en) |
| NZ (1) | NZ503711A (en) |
| PL (1) | PL340294A1 (en) |
| RU (1) | RU2198172C2 (en) |
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| NL88063C (en) | 1950-12-05 | |||
| US4640925A (en) * | 1983-06-02 | 1987-02-03 | Warner-Lambert Company | Diphenylmethylene piperidines, compositions and use |
| US4540780A (en) | 1983-06-02 | 1985-09-10 | Warner-Lambert Company | Diphenylmethylene piperidines |
| ZA914888B (en) * | 1990-06-27 | 1992-04-29 | Sankyo Co | Thiazolidinecarboxylic acid amide derivatives having antiallergic activity,their preparation and their use |
| IL118768A (en) * | 1995-07-12 | 2000-10-31 | Akzo Nobel Nv | Diphenylmethane piperidine derivatives pharmaceutical compositions containing them and a method for their preparation |
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1998
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- 1998-10-07 KR KR1020007003722A patent/KR20010024441A/en not_active Application Discontinuation
- 1998-10-07 CA CA002305277A patent/CA2305277A1/en not_active Abandoned
- 1998-10-07 IL IL13519598A patent/IL135195A0/en unknown
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- 1998-10-07 AU AU21506/99A patent/AU747393B2/en not_active Ceased
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- 2002-01-11 US US10/045,726 patent/US20020087001A1/en not_active Abandoned
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| Publication number | Publication date |
|---|---|
| HUP0004796A3 (en) | 2002-05-28 |
| US20020165395A1 (en) | 2002-11-07 |
| CA2305277A1 (en) | 1999-04-22 |
| KR20010024441A (en) | 2001-03-26 |
| WO1999019324A2 (en) | 1999-04-22 |
| EP1021440A2 (en) | 2000-07-26 |
| NO20001778D0 (en) | 2000-04-06 |
| TR200000916T2 (en) | 2000-07-21 |
| BR9812862A (en) | 2000-08-08 |
| PL340294A1 (en) | 2001-01-29 |
| RU2198172C2 (en) | 2003-02-10 |
| JP2001519430A (en) | 2001-10-23 |
| IL135195A0 (en) | 2001-05-20 |
| NZ503711A (en) | 2002-05-31 |
| HUP0004796A2 (en) | 2002-04-29 |
| WO1999019324A3 (en) | 1999-07-01 |
| NO20001778L (en) | 2000-05-25 |
| AU747393B2 (en) | 2002-05-16 |
| AU2150699A (en) | 1999-05-03 |
| US20020087001A1 (en) | 2002-07-04 |
| US20030149269A1 (en) | 2003-08-07 |
| US6365604B1 (en) | 2002-04-02 |
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